tbuckley/cabot-search huggingface dataset:
An Algorithm for the Operational Assessment of Adverse Drug Reactions
Authors: John M. Leventhal
Journal: JAMA (1979)

To determine how practicing clinicians use a recently developed algorithm for the diagnostic assessment of suspected adverse drug reactions (ADRs), eight clinicians—four board-certified, practicing physicians and four interns—rated the likelihood of 30 suspected ADRs. Each physician reviewed the case summaries, first using implicit clinical judgment and two months later by means of the ADR algorithm. The algorithm significantly improved the reproducibility of the senior clinicians' assessments as compared with their implicit assessments; however, the improvement in the interns' assessments with the algorithm was not significant. The validity of the physicians' assessments, which was measured by comparing their ratings with a consensus rating of the three algorithm developers, was also significantly improved by the use of the algorithm. When used by practicing clinicians, the algorithm improves the reproducibility and validity of their assessments of ADRs and should provide a more precise diagnostic approach to these complex clinical phenomena. (<i>JAMA</i>242:1991-1994, 1979)
Response of Hemiballismus to Haloperidol
Authors: Gordon J. Gilbert
Journal: JAMA (1976)

<h3>To the Editor.—</h3> The recent letter of Dr Michael J. Davis (235:2812, 1976) confirming my initial report (233:535, 1975) of the therapeutic efficacy of haloperidol in the treatment of hemiballismus leads me to report another case. <h3>Report of a Case.—</h3> On April 30, 1976, a 72-year-old hypertensive woman who had received anticoagulant therapy one month earlier because of pulmonary emboli was seen with a five-day history of severe hemiballismic movements of the right extremities. Large ecchymotic areas covered her right arm, the result of its constant traumatic beating against nearby objects. She could at times hold the right hand down by sitting on it, but when not so restrained, it flailed constantly about, most conspicuously in a series of rotary movements at the shoulder. Two-point discrimination was impaired in the right finger-tips, figure writing in the hand, and position sense in the great toe. There were no other abnormalities seen
Immunization by Selective Infection With Type 4 Adenovirus Grown in Human Diploid Tissue Culture
Authors: Robert M. Chanock
Journal: JAMA (1966)

Numerous studies have shown that adenovirus infection constitutes a major cause of acute febrile respiratory-tract disease in military recruits.<sup>1,2</sup>Most recruit adenovirus infections are produced by type 4 virus, and to a lesser extent by types 3 and 7 viruses. The impact of adenovirus infection on recruit populations is large in terms of high respiratory-tract disease morbidity, hospitalization, and costly disruption of military training.<sup>3</sup>For this reason there is an urgent need for effective immunoprophylaxis. The first experimental inactivated adenovirus vaccines prepared in monkey-kidney tissue culture were extremely effective in preventing adenovirus disease.<sup>4,5</sup>However, subsequent production lots of similar vaccines exhibited a variable degree of potency. In some instances very little protection was conferred.<sup>3</sup> In addition there has been considerable difficulty in producing adenovirus vaccines which are free of simian virus contamination. The most troublesome of the simian viruses has been simian virus 40 (SV 40).
Letter to the Editor: The pathological impact of PAR2 on hepatic insulin resistance
Authors: Hsien-Hui Chung
Journal: Hepatology (2023)

To the editor, Hepatic insulin resistance was correlated with diabetes and the progression of NAFLD. In the latest article published by Shearer et al.,1 the authors have demonstrated that protease-activated receptor 2 (PAR2) exerted impaired glucose uptake, glycogen storage, and insulin resistance by the suppression of the major hepatic glucose transporter, GLUT2, through Gq-MAPK-FoxA3 and the inhibition of insulin-Akt signaling through Gq-calcium-CaMKK2 pathways, which were reversed by a liver-homing pepducin, PZ-235. Nevertheless, I have some insights concerning the pathological mechanisms of PAR2 in hepatic insulin resistance. First, the current study mainly investigated the influence of PAR2 on hepatic glycogen synthesis but not hepatic gluconeogenesis and lipid metabolism. Notably, the expressions of G6Pase, PEPCK, SREBP-1c, and FAS involved in gluconeogenesis and lipogenesis were reduced in HFD-fed Par2−/− mice.2 Thus, enhanced hepatic glycogen synthesis and suppressed hepatic gluconeogenesis and lipogenesis by inhibiting PAR2 contributed to alleviating hepatic insulin resistance. Second, PAR2-mediated hepatic insulin resistance regarding adipokines was not mentioned, including leptin and adiponectin. Compared with wild-type mice, Db/Db mice had higher PAR2 expressions in liver but no alteration in visceral white adipose tissues in the current study, suggesting PAR2-mediated hepatic insulin resistance related to leptin signaling was liver-specific. In addition, PAR2 expressions were increased in human adipose tissues from obese people compared with lean people, and the reduced adiponection expressions in diet-induced obesity linked to adipose tissue inflammation were reversed by the PAR2 antagonist.3 Thus, the adipokines involved in PAR2-mediated hepatic insulin resistance and metabolic inflammation should be clarified. Third, the role of PAR2 in the modulation of energy utilization is worthwhile to further explore. Because hepatic insulin resistance was associated with the disruption of AMPK activation in NAFLD, PAR2 overexpression in HepG2 cells significantly attenuated AMPK-mediated autophagy and promoted palmitic acid-induced lipid accumulation through enhanced interaction of CAMKKβ with β-arrestin-2.4 Thus, AMPK activity in PAR2-mediated hepatic insulin resistance should be considered. Collectively, the higher expressions of PAR2 serve as the biomarker for the evaluation of hepatic insulin resistance, and how to clarify the pathological mechanisms of PAR2 activation is helpful for us to identify selective PAR2 modulators to improve hepatic insulin resistance associated with diabetes and NAFLD progression.
Reply
Authors: Manal F. Abdelmalek, Lidija Covic, Athan Kuliopulos
Journal: Hepatology (2023)

We thank H.-H. Chung for his interest in our NAFLD study showing that hepatocyte PAR2 promotes impaired glucose uptake by suppressing the glucose transporter GLUT2 and triggers insulin resistance through an Akt interference mechanism.1 These effects could be effectively reversed in severely diabetic mice with a liver-homing PAR2 pepducin or by liver-specific knock-out of PAR2. Dr. Chung brings up the point that global PAR2-deficient mice fed high-fat diet in a nondiabetic model had drops in liver mRNA levels for genes involved in gluconeogenesis (G6P, PEPCK) and lipogenesis (SREBP-1c, FAS) which could conceivably contribute to improving insulin resistance.2 We had previously demonstrated that nondiabetic PAR2-deficient mice fed high-fat diet had significant reductions in nuclear translocation of active SREBP-1c in liver cells that occurred via a PAR2-JNK mechanism.3 Using liver and plasma metabolomics, we also documented that these same PAR2-deficient mice had major increases in β-oxidation of fatty acids and a marked ketogenic shift in liver metabolism resulting in efficient fat breakdown and suppression of obesity.3 Despite lower circulating glucose, liver glucose and glycogen concentrations were significantly elevated indicating suppression of hepatic glycolysis rather than suppression of gluconeogenesis. In fact, these observations led to the current paper that showed that PAR2 deficiency improved glycemic parameters and increased liver glucose uptake and glycogenesis independent of obesity or diabetic status.1 Consistent with the interesting observation by Dr. Chung that PAR2 regulation of adipokines may be liver-specific, our previous work revealed that the PAR2-deficient mice fed high-fat diet had major increases in mRNA expression of the hepatokine FGF21, a signaling molecule induced in ketotic states.3 With regards to the association of PAR2 with AMPK and autophagy through enhanced interaction of CaMKK2 and β-arrestin in HepG2 cells, this is an excellent hypothesis that requires further evaluation in NAFLD and liver metabolism and could be related to our newly described CaMMK2-β-arrestin interference mechanism on insulin-Akt signaling.1 Indeed, we had previously found that PAR2 deficiency caused enhanced AMPK activation in NAFLD livers along with significant upregulation of AMPK targets Pgc1α, Pgc1β, and PPARα.3 AMPK is a master regulator of hepatic insulin resistance and disruption of AMPK would worsen hepatic steatosis and induce NASH. To the extent that PAR2 attenuates the activity of AMPK, a PAR2 inhibitor has the potential to improve NAFLD/NASH as well as other sequelae of metabolic syndrome. This is definitely a high-impact avenue worth pursuing in future clinical trials.
Scrutiny of Hancock’s handling of the pandemic is far from over
Authors: Gareth Iacobucci
Journal: BMJ (2023)

The erstwhile health secretary turned reality TV "star" Matt Hancock is back in the headlines.On Sunday 26 February, Hancock was asked to explain why he appeared to be wearing a signed Newcastle United shirt that he had previously auctioned off to raise money for charity.A Magpies fan since his "Geordie Uncle Dave" used to take him to games when he was young, Hancock had posted a TikTok video 1 (of course he's on TikTok) wearing the shirt shortly before his team lost to Manchester United in the Carabao Cup final.In a swift clarification on his choice of garment 2 he explained that he had sold the shirt for charity but that it was gifted back to him by the person who had bought it.So, aside from his team losing, there wasn't too much harm done.But things took a definite turn for the worse for Hancock on the morning of Wednesday 1 March when 100 000 WhatsApp messages that he had exchanged with ministers and officials during the pandemic were leaked to the Daily Telegraph by the journalist Isabel Oakeshott. 3The most damaging claim from the messages is that, when he was health secretary, Hancock had dismissed expert advice from Chris Whitty, England's chief medical officer, to test anyone going into a care home-from hospital or the community-for covid-19 at the beginning of the pandemic.
Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma
Authors: Alex Frias, Luca Di Leo, Asier Antoranz, Loulieta Nazerai, Marco Carretta, Valérie Bodemeyer, Chiara Pagliuca, Christina Dahl, Giuseppina Claps, Giulio Eugenio Mandelli, Madhavi Dipak Andhari, Maria Pires Pacheco, Thomas Sauter, Caroline Robert, Per Guldberg, Daniel Hargbøl Madsen, Francesco Cecconi, Francesca Maria Bosisio, Daniela De Zio
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Loss of Ambra1 (autophagy and beclin 1 regulator 1), a multifunctional scaffold protein, promotes the formation of nevi and contributes to several phases of melanoma development. The suppressive functions of Ambra1 in melanoma are mediated by negative regulation of cell proliferation and invasion; however, evidence suggests that loss of Ambra1 may also affect the melanoma microenvironment. Here, we investigate the possible impact of Ambra1 on antitumor immunity and response to immunotherapy. Methods This study was performed using an Ambra1-depleted Braf V600E / Pten −/ − genetically engineered mouse (GEM) model of melanoma, as well as GEM-derived allografts of Braf V600E / Pten −/ − and Braf V600E / Pten −/ − / Cdkn2a −/ − tumors with Ambra1 knockdown. The effects of Ambra1 loss on the tumor immune microenvironment (TIME) were analyzed using NanoString technology, multiplex immunohistochemistry, and flow cytometry. Transcriptome and CIBERSORT digital cytometry analyses of murine melanoma samples and human melanoma patients (The Cancer Genome Atlas) were applied to determine the immune cell populations in null or low-expressing AMBRA1 melanoma. The contribution of Ambra1 on T-cell migration was evaluated using a cytokine array and flow cytometry. Tumor growth kinetics and overall survival analysis in Braf V600E / Pten −/ − / Cdkn2a −/ − mice with Ambra1 knockdown were evaluated prior to and after administration of a programmed cell death protein-1 (PD-1) inhibitor. Results Loss of Ambra1 was associated with altered expression of a wide range of cytokines and chemokines as well as decreased infiltration of tumors by regulatory T cells, a subpopulation of T cells with potent immune-suppressive properties. These changes in TIME composition were associated with the autophagic function of Ambra1. In the Braf V600E / Pten −/ − / Cdkn2a −/ − model inherently resistant to immune checkpoint blockade, knockdown of Ambra1 led to accelerated tumor growth and reduced overall survival, but at the same time conferred sensitivity to anti-PD-1 treatment. Conclusions This study shows that loss of Ambra1 affects the TIME and the antitumor immune response in melanoma, highlighting new functions of Ambra1 in the regulation of melanoma biology.
Cost-effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction
Authors: Laura P. Cohen, Nicolas Isaza, Inmaculada Hernandez, Gregory D. Lewis, Jennifer E. Ho, Gregg C. Fonarow, Dhruv S. Kazi, Brandon K. Bellows
Journal: JAMA Cardiology (2023)

Adding a sodium-glucose cotransporter-2 inhibitor (SGLT2-I) to standard-of-care treatment in patients with heart failure with preserved ejection fraction (HFpEF) reduces the risk of a composite outcome of worsening heart failure or cardiovascular mortality, but the cost-effectiveness in US patients with HFpEF is uncertain.
Comparative Genomic and Transcriptomic Analyses Reveal the Impacts of Genetic Admixture in Kazaks, Uyghurs, and Huis
Authors: Yuwen Pan, Jia Wen, Zhilin Ning, Yuan Yuan, Xubing Liu, Yajun Yang, Yaqun Guan, Yan Lu, Dolikun Mamatyusupu, Shuhua Xu
Journal: Molecular Biology and Evolution (2023)

Abstract Population admixture results in the combinations of genetic components derived from distinct ancestral populations, which may impact diversity at the genetic, transcriptomic, and phenotypic levels, as well as postadmixture adaptive evolution. Here, we systematically investigated the genomic and transcriptomic diversity in Kazaks, Uyghurs, and Huis—three admixed populations of various Eurasian ancestries living in Xinjiang, China. All three populations showed elevated genetic diversity and closer genetic distance compared with the reference populations across the Eurasian continent. However, we also observed differentiated genomic diversity and inferred different demographic histories among the three populations. Varying ancestry proportions observed in both the global and local aspects corresponded to the population-differentiated genomic diversity, with the most representative signals observed in the genes EDAR, SULT1C4, and SLC24A5. The varying local ancestry partly resulted from the postadmixture local adaptation, with the most significant signals observed in immunity- and metabolism-related pathways. Admixture-shaped genomic diversity further influenced the transcriptomic diversity in the admixed populations; in particular, population-specific regulatory effects were associated with immunity- and metabolism-involved genes such as MTHFR, FCER1G, SDHC, and BDH2. Furthermore, differentially expressed genes between the populations were identified, many of which could be explained by the population-specific regulatory properties, including genes related to health concerns (e.g., AHI1 between Kazak and Uyghurs [P &amp;lt; 6.92 × 10−5] and CTRC between Huis and Uyghurs [P &amp;lt; 2.32 × 10−4]). Our results demonstrate genetic admixture as a driving force in shaping the genomic and transcriptomic diversity of human populations.
On-Site Computed Tomography–Derived Fractional Flow Reserve to Guide Management of Patients With Stable Coronary Artery Disease: The TARGET Randomized Trial
Authors: Junjie Yang, Dongkai Shan, Xi Wang, Xiaoqing Sun, Meihua Shao, Kan Wang, Yueying Pan, Zhiqiang Wang, U. Joseph Schoepf, Rock H. Savage, Mei Zhang, Mei Dong, Lei Xu, Yujie Zhou, Xiang Ma, Xinyang Hu, Liming Xia, Hesong Zeng, Zinuan Liu, Yundai Chen
Journal: Circulation (2023)

Background: Computed tomography–derived fractional flow reserve (CT-FFR) using on-site machine learning enables identification of both the presence of coronary artery disease and vessel-specific ischemia. However, it is unclear whether on-site CT-FFR improves clinical or economic outcomes when compared with the standard of care in patients with stable coronary artery disease. Methods: In total, 1216 patients with stable coronary artery disease and an intermediate stenosis of 30% to 90% on coronary computed tomographic angiography were randomized to an on-site CT-FFR care pathway using machine learning or to standard care in 6 Chinese medical centers. The primary end point was the proportion of patients undergoing invasive coronary angiography without obstructive coronary artery disease or with obstructive disease who did not undergo intervention within 90 days. Secondary end points included major adverse cardiovascular events, quality of life, symptoms of angina, and medical expenditure at 1 year. Results: Baseline characteristics were similar in both groups, with 72.4% (881/1216) having either typical or atypical anginal symptoms. A total of 421 of 608 patients (69.2%) in the CT-FFR care group and 483 of 608 patients (79.4%) in the standard care group underwent invasive coronary angiography. Compared with standard care, the proportion of patients undergoing invasive coronary angiography without obstructive coronary artery disease or with obstructive disease not undergoing intervention was significantly reduced in the CT-FFR care group (28.3% [119/421] versus 46.2% [223/483]; P &lt;0.001). Overall, more patients underwent revascularization in the CT-FFR care group than in the standard care group (49.7% [302/608] versus 42.8% [260/608]; P =0.02), but major adverse cardiovascular events at 1 year did not differ (hazard ratio, 0.88 [95% CI, 0.59–1.30]). Quality of life and symptoms improved similarly during follow-up in both groups, and there was a trend towards lower costs in the CT-FFR care group (difference, –¥4233 [95% CI, –¥8165 to ¥973]; P =0.07). Conclusions: On-site CT-FFR using machine learning reduced the proportion of patients with stable coronary artery disease undergoing invasive coronary angiography without obstructive disease or requiring intervention within 90 days, but increased revascularization overall without improving symptoms or quality of life, or reducing major adverse cardiovascular events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03901326.
When I use a word . . . . Data—certainly plural, rarely singular
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

The UK newspaper <i>The Financial Times</i> recently instructed its contributors that its style guide has been changed. The word “data” is henceforth to be considered singular. This diktat mandates “data is,” not “data are,” “this data,” not “these data,” and so on. They can’t have been studying the evidence—the etymology of the word, grammatical considerations, and above all usage. Etymologically, the word “data” is the plural form of the Latin word “datum,” something that is given or is due to be given—a present, a debit, or a debt. And that should be the end of it. “Data” is plural. Grammatical analysis supports this usage. However, the etymological fallacy tells us not to assume that the etymology of a word rigidly determines what it means or how it is to be used in English. In computer science “data” implies information, in a technical sense, carried by an electrical current, and “data” can therefore be regarded as singular. However, in common parlance it refers to pieces of information, in a non-technical sense, such as personal characteristics, and is therefore plural. Like a subatomic particle, functioning as either a particle or a wave, “data” can function as either singular or plural, depending on the language game in which it is being used. Since most uses, such as matters discussed in newspapers, involve common parlance, “data” should continue to be regarded as plural, except on the rare occasions when computer science is the specific subject matter.
Gait, physical activity and tibiofemoral cartilage damage: a longitudinal machine learning analysis in the Multicenter Osteoarthritis Study
Authors: Kerry E Costello, David T Felson, S Reza Jafarzadeh, Ali Guermazi, Frank W Roemer, Neil A Segal, Cora E Lewis, Michael C Nevitt, Cara L Lewis, Vijaya B Kolachalama, Deepak Kumar
Journal: British Journal of Sports Medicine (2023)

To (1) develop and evaluate a machine learning model incorporating gait and physical activity to predict medial tibiofemoral cartilage worsening over 2 years in individuals without advanced knee osteoarthritis and (2) identify influential predictors in the model and quantify their effect on cartilage worsening.An ensemble machine learning model was developed to predict worsened cartilage MRI Osteoarthritis Knee Score at follow-up from gait, physical activity, clinical and demographic data from the Multicenter Osteoarthritis Study. Model performance was evaluated in repeated cross-validations. The top 10 predictors of the outcome across 100 held-out test sets were identified by a variable importance measure. Their effect on the outcome was quantified by g-computation.Of 947 legs in the analysis, 14% experienced medial cartilage worsening at follow-up. The median (2.5-97.5th percentile) area under the receiver operating characteristic curve across the 100 held-out test sets was 0.73 (0.65-0.79). Baseline cartilage damage, higher Kellgren-Lawrence grade, greater pain during walking, higher lateral ground reaction force impulse, greater time spent lying and lower vertical ground reaction force unloading rate were associated with greater risk of cartilage worsening. Similar results were found for the subset of knees with baseline cartilage damage.A machine learning approach incorporating gait, physical activity and clinical/demographic features showed good performance for predicting cartilage worsening over 2 years. While identifying potential intervention targets from the model is challenging, lateral ground reaction force impulse, time spent lying and vertical ground reaction force unloading rate should be investigated further as potential early intervention targets to reduce medial tibiofemoral cartilage worsening.